Palliative Non-Operative Management in Geriatric Hip Fracture Patients: When Would Surgeons Abstain from Surgery?

Background: For hip fracture patients with a limited life expectancy, operative and palliative non-operative management (P-NOM) can yield similar quality of life outcomes. However, evidence on when to abstain from surgery is lacking. The aim of this study was to quantify the influence of patient characteristics on surgeons' decisions to recommend P-NOM. Methods: Dutch surgical residents and orthopaedic trauma surgeons were enrolled in a conjoint analysis and structured expert judgement (SEJ). The participants assessed 16 patient cases comprising 10 clinically relevant characteristics. For each case, they recommended either surgery or P-NOM and estimated the 30-day postoperative mortality risk. Treatment recommendations were analysed using Bayesian logistic regression, and perceived risks were pooled with equal and performance-based weights using Cooke's Classical Model. Results: The conjoint analysis and SEJ were completed by 14 and 9 participants, respectively. Participants were more likely to recommend P-NOM to patients with metastatic carcinomas (OR: 4.42, CrI: 2.14-8.95), severe heart failure (OR: 4.05, CrI: 1.89-8.29), end-stage renal failure (OR: 3.54, CrI: 1.76-7.35) and dementia (OR: 3.35, CrI: 1.70-7.06). The patient receiving the most P-NOM recommendations (12/14) had a pooled perceived risk of 30-day mortality between 50.8 and 62.7%. Conclusions: Overall, comorbidities had the strongest influence on participants' decisions to recommend P-NOM. Nevertheless, practice variation and heterogeneity in risk perceptions were substantial. Hence, more decision support for considering P-NOM is needed.

Systematic review and meta-analysis of preoperative predictors for early mortality following hip fracture surgery.

Hip fractures are a global health problem with a high postoperative mortality rate. Preoperative predictors for early mortality could be used to optimise and personalise healthcare strategies. This study aimed to identify predictors for early mortality following hip fracture surgery. Cohort studies examining independent preoperative predictors for mortality following hip fracture surgery were identified through a systematic search on Scopus and PubMed. Predictors for 30-day mortality were the primary outcome, and predictors for mortality within 1 year were secondary outcomes. Primary outcomes were analysed with random-effects meta-analyses. Confidence in the cumulative evidence was assessed using the GRADE criteria. Secondary outcomes were synthesised narratively. Thirty-three cohort studies involving 462,699 patients were meta-analysed. Five high-quality evidence predictors for 30-day mortality were identified: age per year (OR: 1.06, 95% CI: 1.04-1.07), ASA score ≥ 3 (OR: 2.69, 95% CI: 2.12-3.42), male gender (OR: 2.00, 95% CI: 1.85-2.18), institutional residence (OR: 1.81, 95% CI: 1.31-2.49), and metastatic cancer (OR: 2.83, 95% CI: 2.58-3.10). Additionally, six moderate-quality evidence predictors were identified: chronic renal failure, dementia, diabetes, low haemoglobin, heart failures, and a history of any malignancy. Weak evidence was found for non-metastatic cancer. This review found relevant preoperative predictors which could be used to identify patients who are at high risk of 30-day mortality following hip fracture surgery. For some predictors, the prognostic value could be increased by further subcategorising the conditions by severity.

Development of machine learning models to predict cancer-related fatigue in Dutch breast cancer survivors up to 15 years after diagnosis.

PURPOSE: To prevent (chronic) cancer-related fatigue (CRF) after breast cancer, it is important to identify survivors at risk on time. In literature, factors related to CRF are identified, but not often linked to individual risks. Therefore, our aim was to predict individual risks for developing CRF. METHODS: Two pre-existing datasets were used. The Nivel-Primary Care Database and the Netherlands Cancer Registry (NCR) formed the Primary Secondary Cancer Care Registry (PSCCR). NCR data with Patient Reported Outcomes Following Initial treatment and Long-term Evaluation of Survivorship (PROFILES) data resulted in the PSCCR-PROFILES dataset. Predictors were patient, tumor and treatment characteristics, and pre-diagnosis health. Fatigue was GP-reported (PSCCR) or patient-reported (PSCCR-PROFILES). Machine learning models were developed, and performances compared using the C-statistic. RESULTS: In PSCCR, 2224/12813 (17%) experienced fatigue up to 7.6 ± 4.4 years after diagnosis. In PSCCR-PROFILES, 254 (65%) of 390 patients reported fatigue 3.4 ± 1.4 years after diagnosis. For both, models predicted fatigue poorly with best C-statistics of 0.561 ± 0.006 (PSCCR) and 0.669 ± 0.040 (PSCCR-PROFILES). CONCLUSION: Fatigue (GP-reported or patient-reported) could not be predicted accurately using available data of the PSCCR and PSCCR-PROFILES datasets. IMPLICATIONS FOR CANCER SURVIVORS: CRF is a common but underreported problem after breast cancer. We aimed to develop a model that could identify individuals with a high risk of developing CRF, ideally to help them prevent (chronic) CRF. As our models had poor predictive abilities, they cannot be used for this purpose yet. Adding patient-reported data as predictor could lead to improved results. Until then, awareness for CRF stays crucial.

A holistic profile for cancer-related fatigue for women with breast cancer - a qualitative study.

Objective: Cancer- related fatigue (CRF) is one of the most reported long-term effects after breast cancer and severely impacts quality of life. To come towards optimal treatment of multidimensional CRF, the first step is to use a holistic approach to develop a holistic patient profile including the patient's experience and impact of CRF on their life. Methods and measures: Four semi- structured focus groups with twenty- seven breast cancer patients and fourteen interviews with healthcare professionals (HCPs) were held. Reflexive thematic analysis was used to define (sub)themes for the holistic patient profile. The themes of the interviews and focus groups were compared for validity. Results: Breast cancer patients and HCPs described the same five major themes, consisting of experience of CRF, impact and consequences, coping, personality, and CRF treatment. Experience of CRF consists of cognitive, emotional, and physical aspects. Impact and consequences include work, family, partner relation, social contact and hobbies, body, and misunderstanding. Coping consists of twelve (mal)adaptive strategies. Personality and CRF treatment were summarised as themes. Conclusions: A first holistic patient profile was introduced for CRF for breast cancer. This profile can be conceptualized into a questionnaire to collect information for personalized treatment recommendations and monitoring of CRF over time.

Routine and interval detection of locoregional breast cancer recurrences and risk of subsequent distant metastasis.

PURPOSE: Follow-up for breast cancer survivors consists of after care and surveillance. The benefits of routine surveillance visits remain debatable. In this study we compared the severity of locoregional recurrences (LRRs) and the subsequent risk of a distant metastasis (DM) between LRRs detected at routine and interval visits. METHODS: Women diagnosed with early breast cancer between 2003 and 2008 in one of the 15 participating hospitals, and who developed a LRR as first event after primary treatment, were selected from the Netherlands Cancer Registry (Cohort A). Chi-squared tests were used to compare the severity of routine- and interval-detected local recurrences (LRs) and regional recurrences (RRs), using tumor size, tumor grade, and number of positive lymph nodes. Data on the development of a subsequent DM after a LRR were available for a subset of patients (Cohort B). Cohort B was used to estimate the association between way of LRR-detection and risk of a DM. RESULTS: Cohort A consisted of 109 routine- and 113 interval-LRR patients. The severity of routine-detected LRs or RRs and interval-detected LRs or RRs did not significantly differ. Cohort B consisted of 66 routine- and 61 interval-LRR patients. Sixteen routine- (24%) and 17 (28%) interval-LRR patients developed a DM. After adjustment, way of LRR-detection was not significantly associated with the risk of a DM (hazard ratio: 1.22; 95% confidence interval: 0.49-3.06). CONCLUSION: The current study showed that routine visits did not lead to less severe LRRs and did not decrease the risk of a subsequent DM.

Patient preference attributes in eHealth interventions for cancer-related fatigue: A scoping review.

INTRODUCTION: Cancer-related fatigue (CRF) is one of the most reported long-term effects breast cancer patients experience after diagnosis. Many interventions for CRF are effective, however, not for every individual. Therefore, intervention advice should be adjusted to patients' preferences and characteristics. Our aim was to develop an overview of eHealth interventions and their (preference sensitive) attributes. METHODS: eHealth interventions were identified using a scoping review approach. Eligible studies included breast cancer patients and assessed CRF as outcome. Interventions were categorised as physical activity, mind-body, psychological, 'other' or 'combination'. Information was extracted on various (preference sensitive) attributes, like duration, intensity, peer support and costs. RESULTS: Thirty-five interventions were included and divided over the intervention categories. (Preference sensitive) attributes varied both within and between these categories. Duration varied from 4 weeks to 6 months, intensity from daily to own pace. Peer support was present in seven interventions and costs were known for six. CONCLUSION: eHealth interventions exist in various categories, additionally, there is much variation in (preference sensitive) attributes. This provides opportunities to implement our overview for personalised treatment recommendations for breast cancer patients struggling with CRF. Taking into account patients' preferences and characteristics suits the complexity of CRF and heterogeneity of patients.

Mind Your Data: Privacy and Legal Matters in eHealth.

The health care sector can benefit considerably from developments in digital technology. Consequently, eHealth applications are rapidly increasing in number and sophistication. For successful development and implementation of eHealth, it is paramount to guarantee the privacy and safety of patients and their collected data. At the same time, anonymized data that are collected through eHealth could be used in the development of innovative and personalized diagnostic, prognostic, and treatment tools. To address the needs of researchers, health care providers, and eHealth developers for more information and practical tools to handle privacy and legal matters in eHealth, the Dutch national Digital Society Research Programme organized the "Mind Your Data: Privacy and Legal Matters in eHealth" conference. In this paper, we share the key take home messages from the conference based on the following five tradeoffs: (1) privacy versus independence, (2) informed consent versus convenience, (3) clinical research versus clinical routine data, (4) responsibility and standardization, and (5) privacy versus solidarity.

Applying Risk-Based Follow-Up Strategies on the Dutch Breast Cancer Population: Consequences for Care and Costs.

OBJECTIVES: An important aim of follow-up after primary breast cancer treatment is early detection of locoregional recurrences (LRR). This study compares 2 personalized follow-up scheme simulations based on LRR risk predictions provided by a time-dependent prognostic model for breast cancer LRR and quantifies their possible follow-up efficiency. METHODS: Surgically treated early patients with breast cancer between 2003 and 2008 were selected from the Netherlands Cancer Registry. The INFLUENCE nomogram was used to estimate the 5-year annual LRR. Applying 2 thresholds, they were defined according to Youden's J-statistic and a predefined follow-up sensitivity of 95%, respectively. These patient's risk estimations served as the basis for scheduling follow-up visits; 2 personalized follow-up schemes were simulated. The number of potentially saved follow-up visits and corresponding cost savings for each follow-up scheme were compared with the current Dutch breast cancer guideline recommendation and the observed utilization of follow-up on a training and testing cohort. RESULTS: Using LRR risk-predictions for 30 379 Dutch patients with breast cancer from 2003 to 2006 (training cohort), 2 thresholds were calculated. The threshold according to Youden's approach yielded a follow-up sensitivity of 62.5% and a potential saving of 62.1% of follow-up visits and €24.8 million in 5 years. When the threshold corresponding to 95% follow-up sensitivity was used, 17% of follow-up visits and €7 million were saved compared with the guidelines. Similar results were obtained by applying these thresholds to the testing cohort of 11 462 patients from 2007 to 2008. Compared with the observed utilization of follow-up, the potential cost-savings decline moderately. CONCLUSIONS: Personalized follow-up schemes based on the INFLUENCE nomogram's individual risk estimations for breast cancer LRR could decrease the number of follow-up visits if one accepts a limited risk of delayed LRR detection.

Evaluating the Age-Based Recommendations for Long-Term Follow-Up in Breast Cancer.

BACKGROUND: After 5 years of annual follow-up following breast cancer, Dutch guidelines are age based: annual follow-up for women <60 years, 60-75 years biennial, and none for >75 years. We determined how the risk of recurrence corresponds to these consensus-based recommendations and to the risk of primary breast cancer in the general screening population. SUBJECTS, MATERIALS, AND METHODS: Women with early-stage breast cancer in 2003/2005 were selected from the Netherlands Cancer Registry (n = 18,568). Cumulative incidence functions were estimated for follow-up years 5-10 for locoregional recurrences (LRRs) and second primary tumors (SPs). Risks were compared with the screening population without history of breast cancer. Alternative cutoffs for age were determined by log-rank tests. RESULTS: The cumulative risk for LRR/SP was lower in women <60 years (5.9%, 95% confidence interval [CI] 5.3-6.6) who are under annual follow-up than for women 60-75 (6.3%, 95% CI 5.6-7.1) receiving biennial visits. All risks were higher than the 5-year risk of a primary tumor in the screening population (ranging from 1.4% to 1.9%). Age cutoffs <50, 50-69, and > 69 revealed better risk differentiation and would provide more risk-based schedules. Still, other factors, including systemic treatments, had an even greater impact on recurrence risks. CONCLUSION: The current consensus-based recommendations use suboptimal age cutoffs. The proposed alternative cutoffs will lead to a more balanced risk-based follow-up and thereby more efficient allocation of resources. However, more factors should be taken into account for truly individualizing follow-up based on risk for recurrence. IMPLICATIONS FOR PRACTICE: The current age-based recommendations for breast cancer follow-up after 5 years are suboptimal and do not reflect the actual risk of recurrent disease. This results in situations in which women with higher risks actually receive less follow-up than those with a lower risk of recurrence. Alternative cutoffs could be a start toward risk-based follow-up and thereby more efficient allocation of resources. However, age, or any single risk factor, is not able to capture the risk differences and therefore is not sufficient for determining follow-up. More risk factors should be taken into account for truly individualizing follow-up based on the risk for recurrence.

Facilitating validation of prediction models: a comparison of manual and semi-automated validation using registry-based data of breast cancer patients in the Netherlands.

BACKGROUND: Clinical prediction models are not routinely validated. To facilitate validation procedures, the online Evidencio platform ( https://www.evidencio.com ) has developed a tool partly automating this process. This study aims to determine whether semi-automated validation can reliably substitute manual validation. METHODS: Four different models used in breast cancer care were selected: CancerMath, INFLUENCE, Predicted Probability of Axillary Metastasis, and PREDICT v.2.0. Data were obtained from the Netherlands Cancer Registry according to the inclusion criteria of the original development population. Calibration (intercepts and slopes) and discrimination (area under the curve (AUC)) were compared between semi-automated and manual validation. RESULTS: Differences between intercepts and slopes of all models using semi-automated validation ranged from 0 to 0.03 from manual validation, which was not clinically relevant. AUCs were identical for both validation methods. CONCLUSIONS: This easy to use semi-automated validation option is a good substitute for manual validation and might increase the number of validations of prediction models used in clinical practice. In addition, the validation tool was considered to be user-friendly and to save a lot of time compared to manual validation. Semi-automated validation will contribute to more accurate outcome predictions and treatment recommendations in the target population.

Risk-based breast cancer follow-up stratified by age.

Although personalization of cancer care is recommended, current follow-up after the curative treatment of breast cancer is consensus-based and not differentiated for base-line risk. Every patient receives annual follow-up for 5 years without taking into account the individual risk of recurrence. The aim of this study was to introduce personalized follow-up schemes by stratifying for age. Using data from the Netherlands Cancer Registry of 37 230 patients with early breast cancer between 2003 and 2006, the risk of recurrence was determined for four age groups (<50, 50-59, 60-69, >70). Follow-up was modeled with a discrete-time partially observable Markov decision process. The decision to test for recurrences was made two times per year. Recurrences could be detected by mammography as well as by self-detection. For all age groups, it was optimal to have more intensive follow-up around the peak in recurrence risk in the second year after diagnosis. For the first age group (<50) with the highest risk, a slightly more intensive follow-up with one extra visit was proposed compared to the current guideline recommendation. The other age groups were recommended less visits: four for ages 50-59, three for 60-69, and three for ≥70. With this model for risk-based follow-up, clinicians can make informed decisions and focus resources on patients with higher risk, while avoiding unnecessary and potentially harmful follow-up visits for women with very low risks. The model can easily be extended to take into account more risk factors and provide even more personalized follow-up schedules.

Comparison of Logistic Regression and Bayesian Networks for Risk Prediction of Breast Cancer Recurrence.

PURPOSE: For individualized follow-up, accurate prediction of locoregional recurrence (LRR) and second primary (SP) breast cancer risk is required. Current prediction models employ regression, but with large data sets, machine-learning techniques such as Bayesian Networks (BNs) may be better alternatives. In this study, logistic regression was compared with different BNs, built with network classifiers and constraint- and score-based algorithms. METHODS: Women diagnosed with early breast cancer between 2003 and 2006 were selected from the Netherlands Cancer Registry (NCR) ( N = 37,320). BN structures were developed using 1) Bayesian network classifiers, 2) correlation coefficients with different cutoffs, 3) constraint-based learning algorithms, and 4) score-based learning algorithms. The different models were compared with logistic regression using the area under the receiver operating characteristic curve, an external validation set obtained from the NCR from 2007 and 2008 ( N = 12,308), and subgroup analyses for a high- and low-risk group. RESULTS: The BNs with the most links showed the best performance in both LRR and SP prediction (c-statistic of 0.76 for LRR and 0.69 for SP). In the external validation, logistic regression generally outperformed the BNs in both SP and LRR (c-statistic of 0.71 for LRR and 0.64 for SP). The differences were nonetheless small. Although logistic regression performed best on most parts of the subgroup analysis, BNs outperformed regression with respect to average risk for SP prediction in low- and high-risk groups. CONCLUSIONS: Although estimates of regression coefficients depend on other independent variables, there is no assumed dependence relationship between coefficient estimators and the change in value of other variables as in the case of BNs. Nonetheless, this analysis suggests that regression is still more accurate or at least as accurate as BNs for risk estimation for both LRRs and SP tumors.

Shifting breast cancer surveillance from current hospital setting to a community based setting: a cost-effectiveness study.

BACKGROUND: This study explores the effectiveness and cost-effectiveness of surveillance after breast cancer treatment provided in a hospital-setting versus surveillance embedded in the community-based National Breast Cancer Screening Program (NBCSP). METHODS: Using a decision tree, strategies were compared on effectiveness and costs from a healthcare perspective over a 5-year time horizon. Women aged 50-75 without distant metastases that underwent breast conserving surgery in 2003-2006 were selected from the Netherlands Cancer Registry (n = 14,093). Key input parameters were mammography sensitivity and specificity, risk of loco regional recurrence (LRR), and direct healthcare costs. Primary outcome measure was the proportion true test results (TTR), expressed as the positive and negative predictive value (PPV, NPV). The incremental cost-effectiveness ratio (ICER) is defined as incremental costs per TTR forgone. RESULTS: For the NBCSP-strategy, 13,534 TTR (8 positive; 13,526 negative), and 12,923 TTR (387 positive; 12,536 negative) were found for low and high risks respectively. For the hospital-based strategy, 26,663 TTR (13 positive; 26,650 negative) and 24,883 TTR (440 positive; 24,443 negative) were found for low and high risks respectively. For low risks, the PPV and NPV for the NBCSP-based strategy were 3.31% and 99.88%, and 2.74% and 99.95% for the hospital strategy respectively. For high risks, the PPV and NPV for the NBCSP-based strategy were 64.10% and 98.87%, and 50.98% and 99.71% for the hospital-based strategy respectively. Total expected costs of the NBCSP-based strategy were lower than for the hospital-based strategy (low risk: €1,271,666 NBCSP vs €2,698,302 hospital; high risk: €6,939,813 NBCSP vs €7,450,150 hospital), rendering ICERs that indicate cost savings of €109 (95%CI €95-€127) (low risk) and €43 (95%CI €39-€56) (high risk) per TTR forgone. CONCLUSION: Despite expected cost-savings of over 50% in the NBCSP-based strategy, it is nearly 50% lower accurate than the hospital-based strategy, compromising the goal of early detection of LRR to an extent that is unlikely to be acceptable.

Personalisation of breast cancer follow-up: a time-dependent prognostic nomogram for the estimation of annual risk of locoregional recurrence in early breast cancer patients.

The objective of this study was to develop and validate a time-dependent logistic regression model for prediction of locoregional recurrence (LRR) of breast cancer and a web-based nomogram for clinical decision support. Women first diagnosed with early breast cancer between 2003 and 2006 in all Dutch hospitals were selected from the Netherlands Cancer Registry (n = 37,230). In the first 5 years following primary breast cancer treatment, 950 (2.6 %) patients developed a LRR as first event. Risk factors were determined using logistic regression and the risks were calculated per year, conditional on not being diagnosed with recurrence in the previous year. Discrimination and calibration were assessed. Bootstrapping was used for internal validation. Data on primary tumours diagnosed between 2007 and 2008 in 43 Dutch hospitals were used for external validation of the performance of the nomogram (n = 12,308). The final model included the variables grade, size, multifocality, and nodal involvement of the primary tumour, and whether patients were treated with radio-, chemo- or hormone therapy. The index cohort showed an area under the ROC curve of 0.84, 0.77, 0.70, 0.73 and 0.62, respectively, per subsequent year after primary treatment. Model predictions were well calibrated. Estimates in the validation cohort did not differ significantly from the index cohort. The results were incorporated in a web-based nomogram ( http://www.utwente.nl/mira/influence ). This validated nomogram can be used as an instrument to identify patients with a low or high risk of LRR who might benefit from a less or more intensive follow-up after breast cancer and to aid clinical decision making for personalised follow-up.

Survival after locoregional recurrence or second primary breast cancer: impact of the disease-free interval.

The association between the disease-free interval (DFI) and survival after a locoregional recurrence (LRR) or second primary (SP) breast cancer remains uncertain. The objective of this study is to clarify this association to obtain more information on expected prognosis. Women first diagnosed with early breast cancer between 2003-2006 were selected from the Netherlands Cancer Registry. LRRs and SP tumours within five years of first diagnosis were examined. The five-year period was subsequently divided into three equal intervals. Prognostic significance of the DFI on survival after a LRR or SP tumour was determined using Kaplan-Meier estimates and multivariable Cox regression analysis. Follow-up was complete until January 1, 2014. A total of 37,278 women was included in the analysis. LRRs or SP tumours were diagnosed in 890 (2,4%) and 897 (2,4%) respectively. Longer DFI was strongly and independently related to an improved survival after a LRR (long versus short: HR 0.65, 95% CI 0.48-0.88; medium versus short HR 0.81, 95% CI 0.65-1.01). Other factors related to improved survival after LRR were younger age (<70 years) and surgical removal of the recurrence. No significant association was found between DFI and survival after SP tumours. This is the first study to explore the association between the DFI and survival after recurrence in a nationwide population-based cancer registry. The DFI before a LRR is an independent prognostic factor for survival, with a longer DFI predicting better prognosis.